RESEARCH TRIANGLE PARK, N.C.—Final results for a Phase 2 clinical trial are promising for BioCryst Pharmaceuticals Inc., as the company reports on its APeX-1 trial in hereditary angioedema (HAE). APeX-1 was a three-part dose ranging trial to determine the safety, efficacy, tolerability, pharmacokinetics and pharmacodynamics of orally administered once-daily (QD) BCX7353 for 28 days, as a preventative treatment to reduce the frequency of HAE attacks. The final analysis included data from all patients in all three parts of the trial.

HAE is characterized by episodes of severe swelling, which happens most often in the limbs, face, intestinal tract and airway. The swelling often occurs with no known trigger, according to the Genetics Home Reference website (courtesy of the U.S. National Library of Medicine, part of the NIH), but it can also be triggered by minor trauma or stress. Swelling episodes in the intestinal tract cause severe abdominal pain, nausea and vomiting, while swelling in the airway can hamper breathing. Individuals who do not get treatment face an average of one attack every one to two weeks, with most episodes lasting for three to four days, the Genetics Home Reference reports.

According to the U.S. Hereditary Angioedema Association, there are six FDA-approved therapies for preventing and treating HAE attacks. Of those, there are no orally administered options: three are administered intravenously while the other three are administered via subcutaneous injection.

“An effective and tolerable prophylaxis of hereditary angioedema attacks is of paramount importance for many HAE patients and the benefit of an oral administration route for these chronically ill patients cannot be overestimated. In that respect, the results of this trial are extremely encouraging for the HAE patient community,” commented Dr. Emel Aygören-Pürsün, principal investigator for the APeX-1 trial and head of the Interdisciplinary Competence Center for Hereditary Angioedema.

For the final analysis of pooled data from the three parts of the study, 75 participants were randomized and included, consisting of seven at 62.5 mg, 14 at 125 mg, 14 at 250 mg, 18 at 350 mg of BCX7353 QD and 22 who received placebo. The qualifying attack rate was roughly one per week, baseline characteristics were largely well balanced among the treatment groups and compliance with the dosing schedule was excellent (98 percent or higher across all groups). Study participants recorded their symptoms in a diary, and these records were reviewed by an independent expert group. The trial’s primary endpoint was the number of attacks.

Data from the 125 mg dose level showed statistically significant and similar benefit for all attacks, and when differentiated between abdominal and peripheral attacks. At the 250 mg and 350 mg dose levels, no statistically significant effect was seen for abdominal attacks, though such effects were seen on peripheral attacks, a result that led BioCryst to note in a press release that “it is likely that subjects in the 250 mg and 350 mg arms recorded transient drug-related abdominal adverse events as HAE attack symptoms in their diary.” As for the lowest dose level, 62.5 mg QD, no statistically significant differences in attack rates, total or when split, were seen compared to placebo.

The 125 mg dose arm saw a sizable increase in the proportion of attack-free participants compared to placebo—46 percent versus 10 percent—as well as a clinically important and statistically significant improvement in patient quality of life total score. In fact, the mean improvement in this dosing group was more than four times the minimum clinically important difference.

“We are delighted to see a robust treatment effect after completing the largest ever Phase 2 trial in HAE patients. We now have the information necessary to select doses for Phase 3,” said Jon Stonehouse, president and CEO of BioCryst. “The 125 mg once-daily oral dose of BCX7353 provided a high level of efficacy and excellent tolerability. This product profile will be an extremely attractive treatment option for physicians and patients.”

Oral BCX7353 was generally safe and well tolerated, with no new clinically significant safety findings. Steady state BCX7353 plasma levels and kallikrein inhibition levels for this study proved consistent with previous analyses. Promisingly, steady state trough drug levels (24 hours after dosing) of BCX7353 exceeded the proposed target threshold for efficacy of four times the 50-percent effective concentration (EC50) in 0 percent, 64 percent, 100 percent and 100 percent of subjects at the 62.5 mg, 125 mg, 250 mg and 350 mg dose levels, respectively.

The company noted in a presentation of the Phase 2 data that BCX7353’s pharmacokinetics support 175 mg as a likely second dose for Phase 3. BioCryst plans to finalize the design of its Phase 3 and long-term safety trials after meeting with the FDA and the EMA in the fourth quarter of this year, with hopes of initiating both trials in the first quarter of 2018. This program will support its New Drug Application and Marketing Authorization Application submissions for BCX7353.